Managing Coexistent Inflammatory Bowel Disease in Patients with PSC Themos Dassopoulos, M.D. Director, Baylor Center for IBD April 24, 2015

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The Basics! What is IBD? You’re not alone - How common is IBD? It’s not your fault - What causes IBD? What are the symptoms and complications of IBD? Until there is a cure - How is IBD treated? Is IBD different in patients with PSC? Am I what I eat? - What is the role of diet? What is the role of stress? Tips for managing IBD and staying well

Inflammatory Bowel Diseases (IBD) Disorders of chronic bowel inflammation Inappropriate immune reaction to normal bacteria in genetically susceptible individuals

Types of IBD CROHN’S DISEASE (CD) Patchy, full-thickness inflammation Mouth to anus involvement, mostly lower small intestine and colon Fistulas, abscesses, strictures Worsens with smoking Indeterminate Colitis 10%-15% ULCERATIVE COLITIS (UC) Continuous, inflammation of the lining (mucosa) of the colon Colon only

Inflammatory Bowel Diseases (IBD) Disorders of chronic bowel inflammation Inappropriate immune reaction to normal bacteria in genetically susceptible individuals The IBDs are not – Food allergies – Food sensitivities – Infections – Irritable bowel syndrome (IBS)

How common is IBD? 1 to 1.5 million Americans suffer from IBD 80,000 hospitalizations per year 18,000 surgeries per year CD medical costs $18,963 / year UC medical costs $15,020 / year Increasing in the pediatric population Increasing in the developing world

What causes IBD? Inflammation Abnormal gut flora Diet Antibiotics Infections Modifiers: Smoking NSAIDs Defective clearance of bacteria Mucosal inflammatory responses Barrier function of mucosa Environment Genetics Over 150 genes!

Over 160 genes microbial species Multiple environmental factors

Over 160 genes microbial species Multiple environmental factors  Each IBD patient is unique  The course of the disease differs from person to person

Bloody diarrhea False alarms Abdominal pain Ulcerative Colitis

Endoscopic score Ulcerative Colitis

Crohn’s disease

Inflammatory Penetrating Fistulae and Abscesses Stricturing Pain Diarrhea Pain Distension Vomiting Fear of eating Weight loss Rumbling bowel sounds Presentations of Crohn’s Pain Fever Night sweats Weight loss

Inflammatory Penetrating Fistulae and Abscesses Stricturing Pain Diarrhea Pain Distension Vomiting Fear of eating Weight loss Rumbling bowel sounds Presentations of Crohn’s Pain Fever Night sweats Weight loss

Inflammatory Penetrating Fistulae and Abscesses Stricturing Pain Diarrhea Pain Distension Vomiting Fear of eating Weight loss Rumbling bowel sounds Presentations of Crohn’s Pain Fever Night sweats Weight loss

Inflammatory Penetrating Fistulae and Abscesses Stricturing Pain Diarrhea Pain Distension Vomiting Fear of eating Weight loss Rumbling bowel sounds Presentations of Crohn’s Pain Fever Night sweats Weight loss

JointPeripheral arthritis Sacroiliitis Ankylosing spondylitis SkinErythema Nodosum Pyoderma Gangrenosum LiverPrimary Sclerosing Cholangitis EyeEpiscleritis Iritis Extra-intestinal Manifestations

Other complications Anemia (multiple causes) Steroid-dependence Osteoporosis Malabsorption (CD of the small bowel) – Vitamin B12 – Vitamin D Colorectal cancer (UC and CD of the colon) Thrombosis and pulmonary embolism Toxic megacolon

Risk of colon cancer in colitis Risk was greater than 20% in older studies The risk has declined significantly in more recent studies The risk remains high in patients with: – Longstanding pancolitis with significant mucosal injury – PSC: Approximately 30% Patients with PSC and colitis should have an ANNUAL colonoscopy

Clinical features of colon cancer in patients with colitis and PSC Younger at diagnosis of colon cancer More advanced, right-sided colon cancer Possibly higher cancer risk if dominant stenosis The increased risk of colon cancer persists after liver transplantation Patients with PSC and colitis should have an ANNUAL colonoscopy even after liver transplantation

Other complications Anemia (multiple causes) Steroid-dependence Osteoporosis Malabsorption (CD of the small bowel) – Vitamin B12 – Vitamin D Colorectal cancer (UC and CD of the colon) Thrombosis and pulmonary embolism Toxic megacolon

Quality of life Bowel function Depression Work and school attendance Reproductive decisions

Informed, Empowered Patient Prepared Providers Community Health System Self Management Support Clinical Information Systems Decision Support Delivery System Wellness, improved function and quality of life Monitoring and prevention of complications Chronic Care Model Wagner EH Effective Clinical Practice 1998

Goals of Therapy Induction of remission Maintenance of remission Improved quality of life

Goals of Therapy Induction of remission Maintenance of remission Improved quality of life Prevention of complications Restoring and maintaining nutrition Optimization of surgical intervention

Goals of Therapy Induction of remission Maintenance of remission Improved quality of life Prevention of complications Restoring and maintaining nutrition Optimization of surgical intervention Mucosal healing

Mucosal Healing Before therapy After therapy Mucosal Healing results in fewer hospitalizations and surgeries

Classes of IBD therapies Aminosalicylates (UC, CD) Sulfasalazine (Asulfidine  ) Mesalamine (5ASA) (Asacol , Pentasa , Colazal , Lialda , Apriso  ) 5ASA enemas and suppositories (Rowasa enemas , Canasa suppositories  )

Classes of IBD therapies Aminosalicylates (UC, CD) Sulfasalazine (Asulfidine  ) Mesalamine (5ASA) (Asacol , Pentasa , Colazal , Lialda , Apriso  ) 5ASA enemas and suppositories (Rowasa enemas , Canasa suppositories  ) Antibiotics (CD)* Ciprofloxacin (CD) (Cipro  ) Metronidazole (CD)(Flagyl  ) *Antibiotics are used for CD of the colon and to prevent post-operative recurrence of CD. They are not used in UC.

Classes of IBD therapies Aminosalicylates (UC, CD) Sulfasalazine (Asulfidine  ) Mesalamine (5ASA) (Asacol , Pentasa , Colazal , Lialda , Apriso  ) 5ASA enemas and suppositories (Rowasa enemas , Canasa suppositories  ) Antibiotics (CD) Ciprofloxacin (CD) (Cipro  ) Metronidazole (CD)(Flagyl  ) Corticosteroids (UC, CD) Prednisone Budesonide (ileocolic, colonic release) (Entocort , Uceris  ) Rectal (hydrocortisone enemas, foam) ( Cortenema , Cortifoam  ) IV (methyprednisolone,hydrocortisone)

Classes of IBD therapies Immunomodulators 6-mercaptopurine (CD, UC)(Purinethol  ) Azathioprine (CD,UC) (Imuran  ) Methotrexate (CD)

Classes of IBD therapies Immunomodulators 6-mercaptopurine (CD, UC)(Purinethol  ) Azathioprine (CD,UC) (Imuran  ) Methotrexate (CD) Anti-TNF  Infliximab (CD,UC) (Remicade  ) Adalimumab (CD,UC)(Humira  ) Certolizumab (CD)(Cimzia  ) Golimumab (UC)(Simponi  )

Classes of IBD therapies Immunomodulators 6-mercaptopurine (CD, UC)(Purinethol  ) Azathioprine (CD,UC) (Imuran  ) Methotrexate (CD) Anti-TNF  Infliximab (CD,UC) (Remicade  ) Adalimumab (CD,UC)(Humira  ) Certolizumab (CD)(Cimzia  ) Golimumab (UC)(Simponi  ) Anti-  4 integrin Natalizumab (CD)(Tysabri  ) Vedolizumab (UC, CD)(Entyvio  )

Lessons we have learned Treating the disease early gives the best results Adherence to treatment is key Rectal therapies are critical for UC Steroids do not heal the inflammation of CD The most effective medications are – Immunomodulators – Anti-TNF agents – Immunomodulators + anti-TNF (most effective) Benefits far outweigh the risks

The role of surgery in UC Surgery is not necessarily a bad outcome Colectomy cures ulcerative colitis

Proctocolectomy with end-ileostomy

Proctocolectomy with ileal pouch-anal anastomosis Kirat and Remzi, Clin Colon Rectal Surg 2010 Ileum Colon Ileal Pouch

The role of surgery in CD Bowel resection for CD removes the diseased bowel and allows a fresh start BUT, prevent post-operative recurrence

Strictureplasty

Primary Sclerosing Cholangitis in IBD Over 60% of patients with PSC also have IBD: ‒UC 80% ‒CD 10% ‒Indeterminate colitis 10% 3–8% of patients with UC have PSC 1–3% of patients with CD have PSC The activities of IBD and PSC are independent Every patient with PSC should be screened for colitis Treating the IBD does not affect the PSC

Colitis with coexistent PSC is “different” Pancolitis with rectal sparing Mild ileitis Mild activity – occasionally asymptomatic  Less likely to require colectomy because of resistant colitis Increased mortality from colon cancer, liver failure, and cholangiocarcinoma

What happens after liver transplantation? IBD Variable course of colitis Risk of colon cancer remains high Liver Disease Increased risk of PSC recurrence in patients with intact colons The presence or severity of IBD does not influence the occurrence of recurrent PSC or patient survival

What happens after colectomy? After ileal-pouch anal anastomosis Increased risk of pouchitis No increased risk of pouch failure Similar quality of life Higher long-term mortality After end ileostomy Parastomal varices (40-50%)

Diet and IBD The Western diet is one of the causes of IBD No particular food or diet cures IBD Some patients report improved symptoms with specific diets BUT, diets can be restrictive and difficult to follow

Which diet might help prevent IBD? Lower intake of n-6 polyunsaturated fatty acids – Arachidonic acid and Linoleic acid (red meat, margarines, oils derived from soya, sunflower, rapeseed, poppyseed, and corn) Higher intake of n-3 polyunsaturated fatty acids – Perilla oil, fish oil, sardines, salmon Higher intake of dietary fiber Lower intake of sugars

Diet: Specific situations Coexistent conditions – avoid the food culprit – Lactose or fructose intolerance – Celiac disease – Non-celiac gluten sensitivity – Irritable bowel syndrome – FODMAP diet – Food allergies Flares – Bland diet (avoid fat, caffeine, alcohol and fiber) Obstruction – Low residue diet (avoid insoluble fiber: seeds, nuts, beans, green leafy vegetables, wheat bran)

Stress and IBD Many patients report flares precipitated by stress – It’s not only what the patient eats… but also what eats the patient Anxiety, depression, support structures, coping strategies, and perception of illness affect course of illness Patients should be screened for psychological distress Psychological interventions improve quality of life, anxiety and depression

Tips for managing IBD and staying well Educate yourself Learn your disease Come prepared Ask questions Be your own advocate Manage stress and diet Have a plan

Tips for managing IBD and staying well Educate yourself Learn your disease Come prepared Ask questions Be your own advocate Manage stress and diet Have a plan Avoid aspirin and NSAIDs Stop smoking Take your medications Maintain bone health Be vigilant about infection Keep vaccinations up-to-date Get scoped annually (if you have colitis and PSC)

Putting it all together The IBDs are complex diseases – Each patient is unique Chronic disease management – Patient education and empowerment – Collaboration between primary provider, gastroenterologist, hepatologist and other providers The future of IBD care and research is bright!

Additional slides

Aminosalicylates Sulfasalazine Mesalamine (5ASA) 5ASA enemas and suppositories Use: UC, Mild Crohn’s colitis AE: Paradoxical diarrhea, nephrotoxicity

Antibiotics Ciprofloxacin Use: Mild Crohn’s colitis Perianal disease AE:Tendinitis, tendon rupture, C. difficile Metronidazole Use:Mild Crohn’s colitis Prevention of postoperative recurrence Perianal disease AE:Peripheral neuropathy

Corticosteroids Prednisone Budesonide Ileocolic release Colonic release Topical Hydrocortisone enemas, foams and suppositories Budesonide foam IV (methyprednisolone,hydrocortisone) Use:Induction of remission in UC and CD NOT maintenance

Thiopurines Azathioprine  Mercaptopurine Maintenance of steroid induced remission (CD,UC) Perianal disease (CD) Prevention of post-operative recurrence (CD) Reduction of anti-TNF immunogenicity Leukopenia (10-20%)Non-melanoma skin cancer Transaminitis (10-20%)Bacterial infections (with neutropenia) Pancreatitis (3%)Reactivation of HBV Herpes zosterLymphoma (4-6/10,000/year) CMV colitisNodular regenerative hyperplasia

Methotrexate Maintenance of steroid induced remission (CD) Reduction of anti-TNF immunogenicity (CD,UC) Nausea, emesis, fatigue (give folic acid) Stomatitis Leukopenia Liver fibrosis and cirrhosis Interstitial pneumonitis and pulmonary fibrosis Infections are rare No reports of lymphoma

Anti-TNF  Infliximab (Remicade  ), adalimumab (Humira  ), certolizumab pegol (Cimzia  ), golimumab (Simponi  ) Induction and maintenance of remission (CD,UC) Perianal disease (CD) Infusion reactionsCutaneous reactions HepatotoxicityCytopenia Infections: Reactivation of TB, Herpes zoster, HBV Endemic: Histoplasmosis, coccidioidomycosis, blastomycosis Opportunistic: Aspergillosis, cryptococcosis, pneumocystis Melanoma No proof of increased incidence of lymphoma

Anti-TNF  agents Similar efficacy – Induction: ≈ 60% response – Maintenance: ≈ 40% response Similar safety Anti-drug antibodies (ADA) (10-15%/year)  Loss of response Concomitant immunomodulators – Decrease ADA 14.6% on infliximab vs. 0.9% on combo – Enhance efficacy 44.4% on infliximab vs. 58.8% on combo

Similar efficacy in luminal disease – Infliximab is faster-acting Infliximab is more effective for perianal disease Similar safety and immunogenicity Choice of agent also depends on: Cost Convenience Compliance Considerations in selecting anti-TNF 

Anti-Integrin therapies MAdCAM-1 α4β7α4β7 T cell α4β7α4β7

MAdCAM-1 T cell NAT Anti-α 4 Anti-Integrin therapies Natalizumab (Tysabri ® ) Anti-  4 Blocks  4  7 and  4  1 Prohibitive risk of PML if JCV Ab (+)

VED Anti-α 4 β 7 MAdCAM-1 T cell NAT Anti-α 4 Anti-Integrin therapies Natalizumab (Tysabri ® ) Anti-  4 Blocks  4  7 and  4  1 Prohibitive risk of PML if JCV Ab (+) Vedolizumab (Entyvio ® ) Anti-  4  7 Gut specific No risk of PML